The hypothesis that the pancreatic beta cell is a primary site of pathology in human and experimental diabetes, and the knowledge that the beta cell population is affected by genetic background and responds to immunologic and toxic agents, has directed our attention to the need for further study of spontaneous models of diabetes mellitus. This request is for support of research projects designed to study the etiology and pathogenesis of diabetes in a unique model of insulin-dependent diabetes, the Bio Breeding (BB/W) rat. Support is requested for breeding and related physiological experiments designed to establish inbred lines of diabetic BB/W rats and to define the genetic basis of the syndrome. Plasma glucose, immunoreactive insulin, glucose tolerance tests and other metabolic parameters will be monitored as the diabetic syndrome evolves and will be correlated with altered islet structure. The possibility of an immunologic etiology will be studied. Evolving renal glomerular lesions will be followed and correlated with physiologic parameters of diabetic control. Support is requested for projects designed to study the effect of insulin and insulin resistance on liver cell membrane morphology using freeze cleaving techniques. Support is also requested for funds to produce BB/W rats for distribution to other established investigators.